Undecylenic acid and undecylenate antimycotic composition



Patented June 13, 1950 UNDECYLENIC ACID AND UNDECYLENATE ANTIMYCOTICCOIVIPOSITION John C. Baker, Montclalr, N. 3., assignor to Wallace &Tiernan Products, Inc., Belleville, N. J., a corporation of New JerseyNo Drawing. Application April 21, 1945, Serial No. 589,698

The present invention relates to an antimycotic composition useful inthe treatment of superficial fungus infection of humans and higheranimals.

A great deal of research work has been done in the past looking towardthe preparation of suitable therapeutic antimycotic compositions for thetreatment of this type of infection, which is very common among largenumbers of people, and is also at times a serious detriment to thepersonnel in our Armed Forces.

In the past, various materials have been suggested and many actuallyused for the treatment of this type of infection, including, forexample, boric acid, salicylic acid, and sulfur (powder). It has beensuggested to use both saturated and unsaturated fatty acids with variousnumbers of carbon atoms. Zinc salts have also been independentlysuggested for use (see Patent No. 2,190,714) wherein salts of saturatedacids from 3 to 12 carbon atoms are disclosed and wherein zinc salts arealso disclosed. Propionic acid has also been mentioned as a funglstaticagent. In view of the fact that this infection is quite difficult tocontrol and as certain cases respond better to some treatments than toothers: and conversely, as various of those materials above referred tohave better effects on some persons than on others, there is still asubstantial need in the treatment of this type of infection foradditional and more efiective materials, or combinations thereof in thetreatment of many cases of infections of this type. In general, theresults obtained by previously available materials are oftenunsatisfactory and seldom completely satisfactory.

Among the objects of the present invention, therefore, are to provide a.more satisfactory therapeutic composition for the treatment of fungusinfections of the type referred to, which will give superior results ascontrasted with previously available materials and in some instanceswhich will give positively desirable results in cases where thepreviously available materials would not give satisfactory results.

A more specific object of this invention is to provide an antimycoticpreparation, which is compatible with the normal function of the skin,which produces no irritating effects upon the skin, even when used inlarge quantities: and yet which produces a, powerful antimycotic action.

A further detailed object of the present invention is to provide apreparation or composition, which contains an effective antimycotic 24Claims. (01. 167-58) 2 agent in sparingly soluble form from which it maybe slowly liberated.

A further object of the present invention is to provide an antimycoticagent, which, at the same 5 time, is a good drying agent.

Another object of the present invention is to provide an antimycoticagent having physical properties which make it suitable for use as adermatologic dusting powder and which also may be prepared in the formof an ointment without the addition of another solid phase.

One of the well recognized problems in therapeutics is to provide atherapeutic agent in such form that 9, high concentration of the agentis never present in or on the body and yet which provides an even orstationary release of the active agent. This is of particular importancein the case of agents applied to the skin as this organ is verysensitive. It responds to irritating stimuli with an inflammatory typeof reaction, which may in some instances be harmful and may counteractthe beneficial effects of the therapeutic agent. Applying this principleto the present situation, it has been known for a long time that theinert fatty acids have considerable antimycotic properties, yetheretofore these compounds have not been widely used for the treatmentof fungus infections of the skin, for the reason, possibly among others,that if these substances are administered in water soluble form by whichthey might produce a local high concentration on the skin, they may besomewhat irritating thereto. If water soluble salts of these fatty acidsare used, they may in some cases, be

irritating because of the production of an alkaline reaction; while ifthe free fatty acids are used, they may in some cases, cause irritationbecause of an undesired increase in the hydrogen ion concentration; andfinally, high concentrations of both soluble acids and salts may beirritating because of the surface-active characteristics of the compounditself.

While water insoluble agents are as a rule quite inactive or inert inaqueous media, I have discovered that the zinc salts of olefinic acidscontaining from 6 to 12 carbon atoms are active antimycotics, whentested by the usual methods on Sabourauds agar and are also highlyeffective and not irritating when used therapeutically.

Zinc salts of olefinic acids have a tendency to 66 sirable in producinguniform and sustained therapeutic action. Because of these properties,the zinc salts of oleiinic acids are useful components of ointments orpowders intended for the application to body surfaces and are one of theessential ingredients of the compositions in accordance with the presentinvention. oozing body surfaces are benefited by the application offinely divided material which absorbs moisture. While there are otherfinely divided soft powders used and useable for this purpose, includingthe zinc salts of parafiinic acids, the zinc salts of olefinic acids inaddition to their useful function as above set forth are quitesatisfactory in this respect. The use thereof as an ingredient of acomposition of the type herein set forth for the various reasons aboveset forth is a primary feature of the present invention.

The chemical and chemotherapeutic properties of olefinic acids are perse known. as is also the comparison of these properties with those ofcorresponding parafllnic acids. The differences of these properties maypossibly tend to explain to some extent at least, the desirabletherapeutic properties of the zinc salts of the oleflnic acids. Inparticular I have found that they are so inert that they can be appliedto the most sensitive parts of the human skin without causing anysubstantial irritation. This is especially the case if care is takenthat substantially neutral salts of olefinic acids are used. The dryingproperties of these salts are also quite remarkable, which is adesirable characteristic in treating infections of this type. Acid andbasic zinc salts of olefinic acids may also be prepared under properlyselected conditions and are quite useful in certain embodiments of theinvention.

The composition of the present invention may be briefly summarized asfollows: (1) a zinc salt of an olefinic acid having 6 to 12 carbonatoms: (2) an olefinic acid having 6 to 12 carbon atoms; (3) in most,but not all instances, a pharmacologically essentially inert carriersuitable respectively for the preparation of the compound in powder andointment forms; (4) a material, usually somewhat alkaline in character,for neutralizing the acid present to a desired extent and controllingthe pH of the composition in most instances when it is made up in theform of an ointment or paste; and (5) optionally added materials whichmay be totally omitted or varied as hereinafter set forth. These variouscomponents and their particular requirements, limitations, scope andproportions will be hereinafter set forth.

I have found that for the reasons above set forth, one essentialingredient of the compositions in accordance with my present inventionto be a zinc salt of an olefinic acid having 6 to 12 carbon atoms. Inthis connection an acid having 12 carbon atoms, viz. alpha betadodecylenic acid (CHaiCHzhCHzCHCOOH) has been studied as representingone extreme and acids having 6 carbon atoms, viz. alpha beta hexenoicacid (CH:[CH:]2CH:CHCOOH) and omega hexenoic acid (CI-IaICH[CH2]3COOH)have been studied as the other extreme. All are about equallysuccessful; from which I assume that the acids having intermediatenumbers of carbon atoms are similarly appropriate and further that theposition of the double bond is largely, if not wholly, immaterial. Thislast is reinforced by the results of tests using acids having 11 carbonatoms (undecylenic acids) wherein in one case the double bond was in thealpha beta position and in another case, in the omega position. In apresent commercial form of compositions in accordance with the presentinvention an omega unsaturated undecylenic acid i employed. The acidselected in the making of the salt may be straight or branched chain.The straight chain acids have been discussed above. As examples ofbranched chain acids, I have studied the results obtained from the useof the following (all alpha beta unsaturated): alpha beta 4 ethylhexenoic acid cnqomlon-on on-ooon alpha beta 4 ethyl octenoic acidcatwalk-omen on-ooon and alpha beta pentenoic acid having a cyclohexylgroup in the chain CsH11-ECH:l:-CH:CH-COOH From the above I haveconcluded that branched and straight chain compounds are both effective,although the straight chain compounds are preferred as they aresubstantially the more active; and that the presence of a saturatedhydrocarbon ring group does not negative although it may vary to someextent the fungicidal activity of the compound. The proportions in whichthis ingredient is to be used, will be later more apparent from theparticular compositions given in the examples, and is contemplated to befrom an effective amount up to 60% or more. In this connection it hasbeen found that when the composition is prepared in powder form, asubstantially higher proportion of the zinc salt may be used than whenan ointment is prepared. In making ointments, not over 60% of thismaterial is presently contemplated. Specifically, I now prefer to usezinc undecylenate Zn[OOC(CH:) sCHICHa]:

as a particular and preferred embodiment of the invention, although I donot wish to be limited in this respect.

A second major and essential ingredient is an olefinic acid per se,which has from 6 to 12 carbon atoms. This acid is subject to the samelimitations as the anion of the zinc salt above discussed and may be thesame acid as the anion of the zinc salt used or another acid within thedefinition; viz. it may be straight or branched chain; and it may haveits double bond at any place in the chain. The desired proportions ofthis ingredient are from about 0.2% to about 10% with apreferredproportion of about 5%. The 5% limit is presently contemplated asapplying particularly to the powder form, while in ointments as much as10% may be used. Specifically I contemplate the use of undecylenic acidas the preferred member of this class.

The third ingredient, which I consider as usually, but not always,essential in the compositions according to my invention, may be definedonly as a class of materials and is particularly a pharmacologically,essentially inert carrier of any suitable kind, which may constitute thebalance of the proportions, once the other active ingredients have beencombined together in the desired proportions. In the powder form of theinvention this inert carrier may, if desired, be wholly omitted.

When the composition of the invention is to be prepared in powder form,I may use such materials as talc, bentonite, diatomaceous earth, or

titania as this inert pulverulent ingredient or carrier.

when the composition is to be prepared for use as a therapeutic inointment form, I may use any suitable ointment base such as a vanishingcream type of base including a water soluble, high molecular weightsubstance such as the natural gums, tragacanth or acacia, or syntheticmaterials such as those known commercially as Carbowax," or methylcellulose. I also contemplate the use of any desired mixture of naturaland artificial or synthetic, materials in this respect. I may also usedesired amounts, with or in place of these other materials of suchthings as-petrolatum, lanolin, cetyl alcohol and propylene glycol.

The pH control of the composition as a whole is often of majorimportance, asit has been found that compositions having a pH in onerange may be more advantageous in treating a given patient than thosehaving a pH in another range. For this reason I contemplate control ofpH within rather wide limits, that is, from about 3 to about 9 asextreme limit or for the usual cases from about 5 to about 8. However, Ihave found that a, preferred form of the invention, which is useable inmany instances, has even a closer pH control, preferably between 6 and7. a :f

In order to obtain a desired pH in the composition, I contemplate that Imay add a strong or weak base to neutralize a desired amount of the freeacid added as aforesaid and thus adjust the pH to a selected value. Thebase thus added is preferably One which will form with the acid added asaforesaid, a salt which will be water soluble. As a specific embodimentof this feature of the invention I contemplate the use oftriethanolamine, which may be added to the composition, for example, toreact with undecylenic acid, to form a salt thereof and in an amount togive a pH of about 6.5, although other desired values of pH may beattained by the use of appropriate different amounts of triethanolamine.I have found in this respect that the triethanolamine salt of theundecylenic acid is a fairly effective solvent for the other activeingredient, which is preferably used therewith. that is, zincundecylenate. It will be understood, however, that in certain instanceswhere a rather strongly alkaline compo ition is desired, I may even usesuch a strong base as sodium hydroxide.

There are certain other materials, which may be optionally added to thecomposition as set forth hereinabove for giving certain desiredproperties to the composition as a whole. One type of such addedmaterials, which are contemplated in accordance with the presentinvention, is that known as anionic wetting agents including suchmaterials as sodium tetradecyl sulphate, sodium dioctyl sulfo-succinateand commercial materials known under the trade namesof Aresklene,Areskap,Aresket," Duponol, Nekal, and many others.

Also included in the possible variants of the composition are materialssuch as have heretofore been known and/ or used in the treatment ofinfection: of this kind, such, for example, as boric acid, salicylicacid, benzoic acid, sulfur (powder) and certain at least of theparaflinic acids.

In the ointment form of the invention a certain proportion of water may,if desired, be ineluded, which may assist in bringing the composition toa desired consistency.

The following examples of various useful compositions in accordance withthe present invention will illustrate how the various ingredients may becombined together in accordance with the principles hereinabove setforth and to attain desired results, it being understood that certain ofthe compositions may be more desirable in treating certain individualcases than are others.

Example #1 (powder) 20 parts by weight of zinc undecylenate is disbursedwith 2 parts of undecylenic acid in an alcohol solution. The alcohol isevaporated and the powder which is obtained is mixed with '78 parts oftalc until a uniform product results. This mixture is my presentpreferred form as a powder and is an antimycotic composition, which hasbeen found useful in the treatment of mycotic infections of the foot.

Example #2 (powder) parts by weight of zinc undecylenate and 10 parts ofacid zinc undecylenate are mixed with parts of zinc stearate and 55parts of talc until a uniform product is obtained.

Example #3 (powder) An example of a powder having a high content of zincundecylenate and complementary low content of undecylenic acid isPercent Zinc undecylenate 99.5 Undecylenic acid 0.5

Example #4 (ointment) 10 parts by weight of cetyl alcohol, 3 parts eachof white pet-rolatum and lanolin are weighed into a suitable containerand melted by heating to 60 C. They are mixed until a uniform product isobtained. In a separat container 10 parts of propylene glycol and 40parts of water are mixed and heated to to C. The two mixtures areblended. 5 parts of undecylenic acid and enough triethanolamine is addedto bring the pH up to 6.5. 0.5 parts of sodium tetradecyl sulfate aredissolved in benzol and added to a mixture of 20 parts zincundecylenate. The benzol is evaporated and the powder dried. The drypowder is added to the molten mixture of other ingredients and stirred.A soft three phase emulsion type of ointment results which has some ofthe characteristics of a vanishing cream. Sum cient water is 'then addedand mixed until a uniform product of parts by weight is obtained.

1 This composition ma be summarized as folows:

Per cent Undecylenic acid 5 Zinc undecylenate 20 Sodium tetradecylsulfate 0.5 Petrolatum 3 Lanolin 3 Cetyl a cohol 10 Propylene glycol 10Triethanolamine to adjust the pH to 6.5

Water q. s.

This formula represents my present preferred form of ointment, but Ifurther contemplate that the amount of petrolatum, lanolin, cetylalcohol, propylene glycol and water may be varied within reasonablelimits as will be apparent to those skilled in the art and still yield aproduct having a desired consistency. Zinc undecylenate may be variedfrom 10 to 20% and the sodium tetradecyl sulfate (wetting agent) from0.1 to 1% without substantially varying the above composition. Similarlythe undecylenic acid may var from 2 to 10% and the triethanolamine mayvary correspondingly to maintain the pH between 6 and 7 withoutsubstantially changing the above composition from that presentlypreferred as an ointment.

Example (showing a variant of the ointment with a high undecylenic acidcontent) Per cent Undecylenic acid Zinc undecylenate 20 Sodiumtetradecyl sulfate 0.6 Petrolatum 8 Lanolin 3 Cetyl alcohol 10 Propyleneglycol 5 'Ifriethanolamine sufllcient to adjust pH to 6.5 (4%). Water q.s.

Example #6 (illustrating a low concentration of undecylenic acid or theacid ingredient) Per cent Undecylenic acid 0.2 zinc undecylenaie 20Sodium tetradecyl sulfate 0.5 Stearic acid 5 Petrolatum 3 Lanolin 3Cetyl alcohol 10 Propylene glycol 10 Triethanolamine suflicient toadjust pH to 6.5 (1.5 to 2%). Water (1. s.

Example #7 (ointment) An example of an ointment having a high con-Sodium hydroxide suiiicient to adjust pH to 9 (1%). Water q. s.

Example #9 (illustrating a composition where the anion of the zinc saltis difierent from the acid per se used) Per cent Undecylenic acid 5 Zincsalt of alpha beta 4 ethyl hexenoic acid.. 18 Propylene glycol 10"Carbowax 1500" 19 "Carbowax 4000 30 Triethanolamine sumcient to adjustpH to 6.5 (3%). Water q. s.

8 Example #10 (illustrating diflerent acid anions and a low extreme ofpH. This ointment has a pH of approximately 3) I Per cent Alpha betahexenoic acid 10 Zinc undecylenate 18 Propylene glycol 10 Carbowax 1500"21 Carbowax 4000" 30 Water q. s.

Example #11 (illustrating difierent acid anions and without waterpresent) Example #12 (a powder form of the invention with a relativelyhigh concentration' of undecylenic acid) Per cent Undecylenic acid 5Zinc undecylenate 20 Diatomaceous earth 20 Talc Example #13 (similar toExample #12 but with a low concentration of undecylenic acid)Undecylenic acid 0.2 Zinc undecylenate 50 Talc q. s.

Certain of the above examples illustrating extremes in concentrations ofone or another of the ingredients or characteristics, are not asdesirable for average use as some intermediate examples given, but havepositive utility and may be especially desirable in treating certaincases, even to a greater extent than the intermediate compositions,which are usually preferred.

From the above examples, it will be seen that the various ingredientsmay be varied within the teachings hereinabove set forth for making boththe powder and ointment forms of the invention. These examples furtherillustrate the extremes of variations of most of the ingredients andcharacteristics, particularly the essential ingredients and theessential characteristics such as pH.

While it is contemplated that the preferred forms of the invention ashereinabove set forth will be useful in treating average cases, it isspeciflcally contemplated that certain of the more extreme compositionsmay have peculiar utility in certain individual cases. I do not wish tobe limited, therefore, except by the scope of the appended claims, whichare to be construed validly as broadly as the state of the prior artpermits.

What is claimed is:

1. An antimycotic composition, prepared for use as a therapeutic,comprising a zinc salt of an oleflnic acid having from 6 to 12 carbonatoms, and an oleflnic acid having from 6 to 12 carbon atoms, saidsecond named acid being substantially more readily dissoluble in usethan said zinc salt.

2. An antimycotic composition in accordance with claim 1, wherein saidzinc salt is zinc undecylenate.

3. An antimycotic composition in accordance with claim 1, wherein thesecond named olefinic acid i undecylenic acid.

4. An antimycotic composition, prepared for use as a therapeutic,comprising zinc undecylenate, and undecylenic acid, said acid beingsubstantially more readily dissoluble in use than said zincundecylenate.

5. An antimycotic composition in accordance with claim 1, wherein thesecond named olefinic acid is a straight chain compound.

6. An antimycotic composition in accordance with claim 1, wherein saidzinc salt is one of a straight chain olefinic acid, and wherein thesecond named olefinic acid is a straight chain acid.

7. An antimycotic composition in accordance with claim 1, wherein theolefinic acid radical of the zinc salt is the same as the acid radicalof said olefinic acid.

8. An antimycotic composition, prepared for use in powdered form as atherapeutic, comprising a zinc salt of an oleflnic acid having from 6 to12 carbon atoms, an oleflnic acid having from 6 to 12 carbon atoms, anda pulverulent pharmacologically essentially inert carrier material, saidsecond named acid being substantially more readily dissoluble in usethan said zinc salt.

9. An antimycotic composition in accordance with claim 8, wherein saidpulverulent pharmacologically inert carrier material includes at least asubstantial proportion of powdered talc.

10. An antimycotic composition, prepared for use in powder form as atherapeutic, comprising zinc undecylenate, undecylenic acid not overabout and the balance a pulverulent pharmacologically essentially inertcarrier material, said acid being substantially more readily dissolublein use than said zinc undecylenate.

11. An antimycotic composition, prepared for use in a powder form as atherapeutic, comprising about 20% zinc undecylenate, about 2%undecylenic acid, and about 78% talc, said acid being substantially morereadily dissoluble in use than said zinc undecylenate.

12. An antimycotic composition, prepared for usein ointment form as atherapeutic, compris-- ing not over 60% of a zinc salt of an oleflnicacid having from 6 to 12 carbon atoms, an olefinic acid having from 6 to12 carbon atoms, and an alkaline material for reaction at least in partwith said acid in an amount necessary to adjust the pH of thecomposition to a selected value from about 3 to about 9, said at leastpartly neutralized acid being substantially more readily dissoluble inuse than said zinc salt.

13. An antimycotic composition prepared for use in ointment form as atherapeutic, comprising from an effective amount to about of a zinc saltof an olefinic acid having from 6 to 12 carbon atoms, from about 0.2% toabout 10% of an olefinic acid having from 6 to 12 carbon atoms, and abase of a type and present in an amount such as to neutralize said acidat least in part and to form therewith a water soluble salt, said baseserving to predetermine the pH of the composition as a whole at a valuefrom about 3 to about 9, said at least partly neutralized acid, in theform of said water soluble salt, being substantially more readilydissoluble in use than said zinc salt.

14. An antimycotic composition in accordance with claim 12, wherein thepH of the composition is predetermined at a value from about 5 to about8.

15. An antimycotic composition, prepared for use in ointment form as atherapeutic, comprising not over about 60% of a zinc salt of an oleflnicacid having from 6 to 12 carbon atoms, and an olefinic acid having from6 to 12 carbon atoms.

10 said composition having a pH between about 3 and about 9, said secondnamed acid being substantially more readily dissoluble in use than saidzinc salt.

16. An antimycotic composition, prepared for use in ointment form as atherapeutic, comprising as an active ingredient, zinc undecylenatedissolved at least in part'in the triethanolamino salt of undecylenicacid, said composition having a pH from about 5 to about 8, saidtriethanolamine salt being substantially more readily dissoluble in usethan zinc undecylenate.

17. An antimycotic composition, prepared for use in ointment form as atherapeutic, comprising from an effective amount to about 60% or a zincsalt of an oleflnie acid having from 6 to 12 carbon atoms, from about0.2% to about 10% of an olefinic acid having from 6 to 12 carbon atoms,an ointment base which is pharmacologically essentially inert, and abase for neutralizing at least a part of the acid ingredient andadjusting the pH to a desired value from about 3 to about 9, said atleast partly neutralized acid ingredient being substantially morereadily dissoluble in use than said zinc salt.-

18. An antimycotic composition in accordance with claim 17, wherein saidzinc salt is zinc undecylenate, and wherein said olefinic acid, which isintroduced as such is undecylenic acid, and wherein the composition hasa pH from about 5 to about 8.

19. An antimycotic composition, prepared for use in ointment form as atherapeutic, comprising zinc undecylenate irom about 10% to about 20%,undecylenic acid from about 2% to about 10%, an ointment base materialto give a desired consistency to the ointment, and triethanolaminesufficient to adjust the pH to a value between about 6 and about '7,said nndecylenic acid, as

at least in part neutralized by the adjustment of pH withtriethanolamine, being substantially more readily dissoluble in use thansaid zinc undecylenate.

20. An antimycotic composition, prepared for said undecylenic acid, asat least in part neutralized by the adjustment of pH withtriethanolamine, being substantially more readily dissoluble in use thansaid zinc undecylenate.

21. An antimycotic composition, containing as active ingredients, amajor proportion of a. substantially insoluble zinc salt of an oleflnicacid having from 6to 12 carbon atoms, and a minor proportion of acompound containing the anion of an olefinic acid having from 6 to 12carbon atoms, which compound is substantially more readily dissoluble inuse than said zinc salt.

22. An antimycotic composition, containing as active ingredients, amajor proportion of a substantially insoluble zinc salt of an olefinicacid having from 6 to 12 carbon atoms, and a minor proportion of acompound containing the anion 11 of said olefinic acid, which compoundis subetantially more readily dissoluble in use than said zinc salt.

28. An antimycotic composition, containing as active ingredients, amajor proportion 01 zinc undecylenate, and a minor proportion 01' acompound containing the anion of undecylenic acid, which compound issubstantially more readily dissoluble in use than said zincundecylenate.

24. An antimycotic composition, containing as 10 active ingredients,zinc undecylenate, and a compound containing the anion of undecylenicacid, which compound is substantially more readily dissoluble in usethan said zinc undecylenate.

JOHN C. BAKER.

REFERENCES CITED The following reierences are or record in the file 01this patent:

UNITED STATES PATENTS Number Name Date 1,995,663 Bollmann Mar. 26, 198512 Number Name Date 2,190,714 Hofiman Feb. 20, 1940 2,217,905 Holman eta1 Oct. 15, 1940 2,290,710 Rice July 21, 1942 2,314,125 Coca Mar. 16,1943 OTHER REFERENCES New Modern Drugs, Gutman, 16th supplement (October1944), p. 26.

3111]., Johns Hopkins Hoep., December 1944, pages 417 to 421 and 484 to489.

Clinical Medicine, September 1942, page 257.

Food Research, 4 (1939), pages 539 to 545.

Peck et al., J. Investigative Dermatology,

15 August 1938, pages 237, 251, 280, 261, 262.

30 of Scientific Research and Development, dated December 1, 1943.Unclassified 2 pages. Contract No. OEMcmr-334.

1. AN ANTIMYCOTIC COMPOSITION, PREPARED FOR USE AS A THERAPEUTIC,COMPRISING A ZINC SALT OF AN OLEFINIC ACID HAVING FROM 6 TO 12 CARBONATOMS, AND AN OLEFINIC ACID HAVING FROM 6 TO 12 CARBON ATOMS, SAIDSECOND NAMED ACID BEING SUBSTANTIALLY MORE READILY DISSOLUBLE IN USETHAN SAID ZINC SALT.